A recent convergence of findings in humans and animals indicates that our capacity for episodic memory relies on a system of cortical areas and the hippocampus that encode events in the context in which they occur. To understand the information processing mechanisms that underlie episodic memory, we propose a systems analysis that will compare the nature of information processing and identify functional interactions between cortical and hippocampal areas: (1) We will distinguish neural activity with regard to event and context processing in the cortical areas that intimately connected with the hippocampus. (2) We will characterize the functional organization of event and context processing across different subareas within the hippocampus, testing the hypothesis that the dorsal-ventral axis represents distinctions in the specificity of events and scale of context; that CA1 and CA3 represents the similarities and differences between related but distinct events; and that distal-proximal CA1 represents a gradient of selectivity or mixing of object and context information. (3) We will identify key areas critical to object-context association and identify critical interactions between components of the system. Our approach involves a neural systems analysis that combines a behavioral paradigm for associating events and context, multi-site tetrode recording that compares information encoded in multiple areas and identifies their synchronized activity, and reversible muscimol and optogenetic inactivation combined with recording that explores how neural coding in one area depends on other components of the system. The combined information gained from this systems analysis will improve our model of the functional organization of the cortical-hippocampal system and increase our understanding of how episodic memories are stored and retrieved within this system. PUBLIC HEALTH RELEVANCE: Our understanding of cognitive disorders and the eventual development of treatments depends crucially upon an understanding of the cognitive and neural mechanisms that underlie normal cognition. For example, abnormal thought patterns in schizophrenia, as well as other cognitive disorders, reflect an underlying disorganization of the neural machinery that stores and retrieves memories to compose our knowledge of the world and this proposed work will pioneer a new understanding about how memories are represented in neural circuitry and about how neural representations guide cognition in daily life. Because the hippocampus and adjacent cortical areas are compromised in multiple major mental disorders, an understanding of the functional circuitry of these areas is particularly important.